This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Spinal muscular atrophy (SMA) is an autosomal genetic disease caused by deletion or mutation(s) of the survival motor neuron gene 1 (SMN1). The hallmark of SMA is death of spinal motor neurons and muscle paralysis. SMA occurs in 1:6000 live births, and thus is one of the most common genetic causes of infant death. The long-term goal of my research is to understand the mechanism(s) of spinal motor neuron death in SMA and to develop a means to prevent neuronal cell death. Our preliminary studies show that skin fibroblasts from SMA patients display increased sensitivity to some death-promoting stimuli, and primary motor neuron cultures are much more sensitive to this death-promoting stimuli comparing to normal fibroblasts. This has led us to hypothesize that SMN plays a role in cell survival;increased vulnerability of motor neurons to the loss of SMN's survival function leads to motor neuron death in SMA. The objective of this proposal is to systematically analyze composition of SMN complexes in motor neurons that are likely responsible for motor neuron survival. This could lead to answer a critical question for understanding SMA pathogenesis, which is why reduced levels of the ubiquitously expressed SMN protein selectively affect motor neurons. Here, we will leverage our expertise in cell death mechanism and motor neuron biology in combination with cutting edge proteomics at Delaware Biotechnology Institute proteomics core directed by Dr. Kelvin Lee to dissect the SMN complexes in motor neurons. We will achieve this in the following aims: 1) determine the composition of SMN complexes in motor neurons, 2) determine distribution of SMN complexes in subcellular compartments in motor neurons, and 3) determine if reduced levels of SMN cause defective SMN complex formation in motor neurons. The results from the proposed studies will provide insight into the mechanism(s) by which SMN function specifically in motor neurons and how SMN-deficiency leads to SMA phenotype. Ultimately, the information obtained could lead to development of therapeutic strategies to intervene.
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